Two-dimensional free-energy surface on the exchange reaction of alkyl chloride/chloride using the QM/MM-MC method

Two-dimensional free-energy surfaces are calculated for alkyl chloride/chloride exchange/inversion reactions: Cl^- + RCl (R = Me and t-Bu) surrounded by one hundred H₂O molecules as a model of solvent. The methodology of free-energy calculation by perturbation theory based on a mixed-Hamiltonian model (QM/MM) combined with Monte Carlo sampling of the solvent configurations was used to obtain the changes in solvation free energy. We devised a special procedure to analyze the two-dimensional free-energy surfaces to gain unique insight into the differences in the reaction mechanisms between the two systems. The inversion reaction path for R = t-Bu on the free-energy surface is found to proceed in an asynchronous way within a concerted framework via the ion-pair region. This is in contrast to the R = Me system that proceeds as a typical S_N2 reaction.